2-Ketoamidines

ABSTRACT

The present invention relates to amidino ketones of the formula   WHEREIN R1 is alkyl of 1 to 4 carbon atoms, phenyl or substituted phenyl, and R2 is alkyl of 1 to 4 carbon atoms, or R1 and R2 together are -(CH2)n-, wherein n is an integer from 2 to 7, AND R3 is alkyl of 1 to 4 carbon atoms, or R1, R2 and R3 together with the carbon atom to which they are bound form the adamantyl radical, R4 is alkyl of 1 to 8 carbon atoms, alkenyl of 2 to 8 carbon atoms, alkoxyalkyl of 2 to 8 carbon atoms in the aggregate thereof, cyanoalkyl wherein the alkyl radical is of 1 to 5 carbon atoms, or a group of formula   WHEREIN R7 and R8 are the same or different and each is alkyl of 1 to 4 carbon atoms, or R7 and R8 together with the nitrogen atom are a heterocyclic ring, or a heterocyclic ring having a ring oxygen atom, and R5 and R6 are the same or different and each is alkyl of 1 to 8 carbon atoms, alkenyl of 2 to 8 carbon atoms, alkoxyalkyl of 2 to 8 carbon atoms in the aggregate thereof or cyanoalkyl wherein the alkyl is of 1 to 5 carbon atoms, or one of R4, R5 and R6 is phenyl or substituted phenyl and the others of R4, R5 and R6 are as defined above, useful as hypoglycaemic agents.

United States Patent [191 Heffe 1 May 20, 1975 Z-KETOAMIDINES [75] Inventor: Wilhelm Heffe,Neuenegg,

Switzerland [73] Assignee: Sandoz Ltd., Basel, Switzerland [22] Filed: Dec. 13, 1973 21 App]. No.: 426,714

Related U.S. Application Data [63] Continuatiomin-part of Ser. No. 366,681, June 4,

[30] Foreign Application Priority Data June 7, 1972 Switzerland 8443/72 Feb. 28, 1973 Switzerland 2917/73 [52] U.S. Cl... 260/564 R; 260/247.5 R; 260/268 N; 260/29378; 260/307 R; 260/326.86;

[51] Int. Cl. C07c 123/00 [58] Field of Search 260/564 R, 501.14

[56] References Cited OTHER PUBLICATIONS Chemical Abst. Vol. 73, Column 130,940(z), (1970).

Primary Examiner-Leon Zitver Assistant Examiner-Gerald A. Schwartz Attorney, Agent, or FirmGerald D. Sharkin; Robert J. Honor; Thomas O. McGovern [57] ABSTRACT The present invention relates to amidino ketones of the formula wherein R is alkyl of l to 4 carbon atoms, phenyl or substituted phenyl, and R is alkyl of 1 to 4 carbon atoms, or R and R together are (CI'I wherein n is an integer from 2 to 7, and

R is alkyl of l to 4 carbon atoms, or R R and R together with the carbon atom to which they are bound form the adamantyl radical, R is alkyl of 1 to 8 carbon atoms, alkenyl of 2 to 8 carbon atoms, alkoxyalkyl of 2 to 8 carbon atoms in the aggregate thereof, cyanoalkyl wherein the alkyl radical is of 1 to 5 carbon atoms, or a group of formula wherein R and R are the same or different and each is alkyl of 1 to 4 carbon atoms, or R and R together with the nitrogen atom are a heterocyclic ring, or a heterocyclic ring having a ring oxygen atom, and R and R are the same or different and each is alkyl of l to 8 carbon atoms, alkenyl of 2 to 8 carbon atoms, alkoxyalkyl of 2 to 8 carbon atoms in the aggregate thereof or cyanoalkyl wherein the alkyl is of l to 5 carbon atoms, or one of R R and R is phenyl or substituted phenyl and the others of R R and R are as defined above, useful as hypoglycaemic agents.

97 Claims, No Drawings Z-KETOAMIDINES IMPROVEMENTS IN OR RELATING TO ORGANIC COMPOUNDS This application is a contination-in-part of our copending application Ser. No. 366,681 filed June 4, I973.

This present invention relates to amidino ketones, especially 3-oxo-butanamidine derivatives.

The invention provides compounds of formula I,

wherein R is alkyl of l to 4 carbon atoms, phenyl or substi-.

tuted phenyl, and

R is alkyl of l to 4 carbon atoms, or

R, and R together are (CH wherein n is an integer from 2 to 7,

and

R is alkyl of l to 4 carbon atoms, or

R R and R together with the carbon atom to which they are bound form the adamantyl radical,

R is alkyl of l to 8 carbon atoms, alkenyl of 2 to 8 carbon atoms, alkoxyalkyl f 2 to 8 carbon atoms in the aggregate thereof, cyanoalkyl wherein the alkyl radical is of l to 5 carbon atoms, or a group of formula wherein R and R are the same or different and each is alkyl of l to 4 carbon atoms, or

R and R together with the nitrogen atom are a heterocyclic ring, or a heterocyclic ring having a ring oxygen atom, and R and R are the same or different and each is alkyl of l to 8 carbon atoms, alkenyl of 2 to 8 carbon atoms, alkoxyalkyl of 2 to 8 carbon atoms in the aggregate thereof or cyanoalkyl wherein the alkyl is of l to 5 carbon atoms, or one of R R and R is phenyl or substituted phenyl and the others of R R and R are as defined above.

When in formula I R or one of the substituents R,,, R and R is a substituted phenyl group, the substituted phenyl group preferably is alkylphenyl, the alkyl radical having from I to 4 carbon atoms, especially methylphcnyl, the alkyl substituent being preferably in the p position, or halophenyl, especially chlorophenyl, the halo substituent being preferably in the p position.

When R,- and R, together with the nitrogen atom are a heterocyelic ring, this is preferably a five or six membered heterocyelic ring, preferably saturated e.g., morpholine. pyrrolidine or piperazine.

Further, in accordance with the invention a compound of formula I may be obtained by a process comprising desulphurizing a compound of formula II,

R N-R 1 4 R -C-CO-CII -S-C R wherein R to R are as defined above.

The process according to the invention may be effected in the presence of a desulphurizing agent, preferably triaryl derivatives, trialkyl derivatives or mixed alkyl/triaryl derivatives wherein each of the alkyl groups preferably is of l to 4 carbon atoms, of phosphorous, arsenic, antimony or bismuth, especially, however, of phosphorus or arsenic. Especially preferred are the phosphorus derivatives. Preferred examples of desulphurizing agents are triphenylphosphine or arsine and triethyl-phosphite.

The process according to the invention may be effected in the absence of a solvent or in an inert organic solvent, e.g., dimethyl formamide, dioxane or dimethyl acetamide. However, the reaction is preferably effected in the absence of a solvent. The reaction temperature may be from to C. After the reaction is complete, the reaction mixture may be acidified, e.g., with an acid capable of forming a water-soluble acid addition salt form of the compound of formula I, e.g., hydrobromic acid, the residue is conveniently filtered off and the resulting acid addition salt form of the compound of formula I is conveniently isolated from the resulting reaction mixture in known manner, e.g., by concentrating by evaporation, and may be purified, e.g., by recrystallization.

Free base forms of compounds of formula I may be converted into acid addition salt form in conventional manner, and vice versa.

Examples of suitable acids for acid addition salt formation are the hydrohalic acids such as hydrochloricand hydrobromic acid, or perchloric acid, and organic acids such as oxalic acid and maleic acid.

The compounds of formula II, used as starting materials in the above process, may be obtained by reacting a reactive ester of an alcohol of formula III,

2 III wherein R to R are as defined above.

In the above reaction the compounds of formula IV react in their tautomeric form of formula lVa,

R IVa wherein R to R are as defined above.

Suitable reactive esters of the alcohol of formula III, include esters of hydrohalic acids, e.g., hydrobromic or hydrochloric acid, or the tosylate. The reaction may be effected either in the absence of a solvent or in an inert organic solvent, e.g., a lower alcohol of l to 6 carbon atoms, acetone, or a cyclic or straight chain ether such as dioxane, tetrahydrofuran or diisopropyl ether. The reaction temperature conveniently is from to 100C. Free base forms of the resulting compounds of formula II are liberated from the acid addition salt forms in known manner, e.g., by treatment with an aqueous alkali metal hydroxide solution.

The compounds of formulae III and IV, used as starting materials in the above process, are either known or may be produced in known manner from known starting materials, for example a compound of formula IV wherein R R and R are alkyl may be obtained by reacting an alkylisothiocyanate with a dialkyl amine in conventional manner.

In so far as the production of the starting material is not particularly described, these compounds are known or may be produced and purified in accordance with standard procedures.

The compounds of formula I are useful because they possess pharmacological activity in animals. In particular the compounds are useful as hypoglycaemic agents as indicated by a lowering of the blood sugar content in the blood of rats on p.o. administration of from 100 to 300 mg/kg animal body weight, of the compounds, in accordance with the following test:

The compound to be tested is administered in increasing doses to groups of 5 to 10 animals. 2 hours after administration, a blood sample is taken from each animal, and the glucose content in the blood serum is established using the ferric cyanide test. The blood sugar lowering effect is determined by a comparison with a control group of 5 to 10 animals to which is administered a physiological common salt solution.

For the above mentioned use the dosage will, of course, vary depending on the compound employed, mode of administration and condition to be treated. However, in general, satisfactory results are obtained when administered at a daily dosage of from 1.5 mg to about 300 mg per kg animal body weight, conveniently given in divided doses 2 to 4 times a day or in sustained release form. For the larger mammals, the total daily dosage is in the range from about 100 to about 1,000 mg, and dosage forms suitable for oral administration comprise from about mg to about 500 mg of the compounds admixed with a solid or liquid pharmaceutical carrier or diluent.

Specific Examples of daily dosages, at which satisfactory results are obtained on p.o. administration are:

i. Compound of Example 46 from 30 to mg/kg animal body weight for rats, and for the larger mammals from about 100 mg to about 1,000 mg.

ii. Compound of Example 14 from 30 to 100 mg/kg animal body weight for rats, and for the larger mammals from about 100 mg to about 1,000 mg;

and iii. Compound of Example 68 from 30 to 100 mg/kg animal body weight for rats, and for the larger mammals from about 100 mg to about 1,000 mg.

As the free base forms of the compounds of formula I are usually oily at room temperature, the compounds are conveniently administered in pharmaceutically acceptable acid addition salt forms which have the same order of activity as the free base forms, and which are readily prepared in conventional manner. Representative acid addition salt forms include organic acid salt forms such as the hydrogen maleate, fumarate, tartrate and methane sulphonate and mineral acid salt forms such as the hydrochloride, hydrobromide and sulphate. A pharmacetical composition may comprise a compound of formula I, in free base form or in pharmaceutically acceptable acid addition salt form, in association with a pharmaceutical carrier or diluent. Such compositions may be prepared by conventional techniques to be in the form of, for example, capsules, tablets, suppositories, suspensions or solutions, for enteral or parenteral administration. Aside from the usual pharmaceutical diluents or carriers, e.g., water, alcohols, natural or hardened oils and waxes, these pharmaceutical compositions may contain suitable preserving, stabilizing, wetting, solubilizing, sweetening, flavouring or colouring agents.

An example of a tablet composition comprises 136 mg of N -butyl-N ,N -diallyl-4,4-dimethyl-3-oxopentanamidine hydrobromide, 1 mg of magnesium stearate, 4 mg of polyvinyl pyrrolidone, 0.5 mg of dimethyl silicone oil, 5 mg of talc, 10 mg of maize starch, 137.8 mg of lactose and 1.5 mg of polyethylene glycol 6,000

The tablets are produced in conventional manner and are provided with a double slit.

In a preferred class of compounds, R R and R are independently alkyl, R is alkyl, alkenyl, phenyl, or substituted phenyl and R and R are, independently, alkyl, alkenyl, alkoxyalkyl or cyanoalkyl. More especially R R and R are alkyl, especially methyl, and R R and R are independently alkenyl especially of 3 to 4 carbon atoms or especially alkyl of 1 to 4 carbon atoms.

In another preferred class of compounds R and R are identical.

In another class of compounds R is phenyl or substituted phenyl and R is alkyl, or R and R together are (CI-I and R is alkyl, or R R and R together with the carbon atom to which they are bound form the adamantyl radical, R, is a group of formula;

wherein R and R are the same or different and each is alkyl of l to 4 carbon atoms, or

R and R together with the nitrogen atom are a heterocyclic ring, or a heterocyclic ring having a ring oxygen atom, and

R and R are phenyl or substituted phenyl.

in the following non-limitative Examples the temperatures are indicated in degrees Centigrade, room temperature is between and C, unless otherwise indicated. The commonly used vacuum is between 8 and 20 mm of Hg, unless otherwise indicated.

EXAMPLE 1 N ,N ,N -triethyl-4,4-dimethyl-3-oxo-pentanamidine a. N,N ,N -triethyl-5,5-dimethyl-4-oxo-2- thiahexanamidine A mixture of 14.3 g of bromopinacoline, 12.8 g of N,N ,N -triethyl thiourea and 120 cc of acetone is heated to the boil at reflux for 8 hours. The reaction mixture is subsequently concentrated by evaporation in a vacuum. cc of an aqueous 1 N sodium hydroxide solution are added to the resulting residue, and the resulting mixture is extracted with diethyl ether. The ethereal solution is dried with potassium carbonate and is subsequently concentrated by evaporation. N,N ,N triethyl-5,5-dimethyl-4-oxo-2-thiahexanamidine is obtained as oily residue.

b. N,N ,N -triethyl-4,4-dimethyl-3-oxo-pentanamidine 13.5 g of the oily N ,N ,N -triethyl-5,5-dimethyl-4- oxo-2-thiahexanamidine obtained in section (a) are mixed with 13.5 g of triphenyl phosphine, and the mixture is heated in an oil bath to 120 for 6 hours in a flask provided with an upright tube. The reaction mixture is subsequently cooled and triturated with l N hydrobromic acid until the acid reaction is maintained. The undissolved triphenyl phosphine sulphide is filtered off and washed with water. The aqueous filtrate is extracted with diethyl ether and purified with charcoal. After the charcoal is filtered off, the aqueous filtrate is evaporated to dryness in a vacuum. After recrystallization from 2 parts by volume of isopropanol/g of compound. or from 4.5 parts by volume of acetone/g of compound, the resulting N,N ,N -triethyl-4,4- dimethyl-3-oxo-pentanamidine hydrobromide has a M.P. of l38-140.

Treatment of the hydrobromide with an aqueous 2 N sodium hydroxide solution, extraction of the alkaline solution with diethyl ether and concentration by evaporation of the ethereal mixture yields oily N ,N ,N triethyl-4,4-dimethyl-3-oxo-pentanamidine.

a. N ,N -di-isobutyl-N -methyl thiourea N ,N -di-isobutyl-4-oxo-2-thia-N,5,S-trimethylhexanamidine hydrobromide 19.5 g of N ,N -di-isobutyl-N -methyl thiourea are dissolved in cc of acetone, and 17.3 g of bromopinacoline are added to the solution. The resulting mixture is allowed to stand at 20 for 12 hours. The mixture is subsequently heated to the boil for 4 hours, is subsequently cooled, and the resulting precipitate is filtered off. The N ,N -di-isobutyl-4-oxo-2-thia-N,5,5-

trimethylhexanamidine hydrobromide, obtained as filter residue, has a M.P. of 202-204.

c. N ,N -di-isobutyl-N ,4,4-trimethyl-3-oxopentanamidine l 1.8 g of N ,N -di-isobutyl-4-oxo-2-thia-N,5,5- trimethyl-hexanamidine (obtained from the hydrobromide by treatment with caustic soda solution and extraction of the liberated base with ether) are heated to for 8 hours together with 12.5 g of triphenyl arsine. The resulting melted material is neutralized with l N hydrobromic acid (about 28 cc); The aqueous solution is poured off and cold alcohol is added to the smeary crystalline product until the solid components are filterable. Filtration is subsequently effected. The filter residue contains about 1 1.6 g of a mixture of triphenyl arsine and triphenyl arsine sulphide. The filtrate is extracted with 100 cc of diethyl ether, and the aqueous solution is concentrated by evaporation in a vacuum. The evaporation residue is heated to 80 together with cc of ethyl acetate, whereby after initial solution crystals are formed. Cooling is then effected to 0, and the residue N ,N -di-isobutyl-N ,4,4-trimethyl-3- oxo-pentamidine hydrobromide (M.P. l51l56) is filtered off.

The compounds of formula 1, indicated in the following Tables, are obtained by using the processes exemplified in the above Examples 1 and 2 and the corresponding starting materials. The indicated melting points refer to the corresponding salt forms. The. free base forms of the compounds of formula 1 are obtained from the salt forms in known manner, e.g., by treat- 55 ment with caustic soda solution and extraction with EXAMPLE 2 ether. iy m y1-3-0 0- The substituents are in the w-position except where pentanamidine. otherwise stated.

Example R R R,-, R R R M.P. Salt form 3 Methyl Methyl Methyl Methyl Methyl Methyl 197- 1 99 Bromide 4 Methyl Methyl Methyl Methyl Methyl Ethyl 174 1 75 Bromide 5 Methyl Methyl Methyl Methyl Ethyl Ethyl 1 67 Bromide 6 Methyl Methyl Methyl Methyl fi-CH o-ethyl fl-CH Oethyl 130-1 3 1 Bromide 7 Methyl Methyl Methyl Methyl Propyl Propyl -1 77 Bromide 8 Methyl Methyl Methyl Methyl lsopropyl lsopropyl 160 l 6 1 Bromide 9 Methyl Methyl Methyl Methyl Allyl Allyl 8890 Bromide 4 l0 Methyl Methyl Methyl Methyl Butyl Butyl 1 19-1 20 Bromide l 1 Methyl Methyl Methyl Methyl lsobutyl lsobutyl l55l57 Bromide l2 Methyl Methyl Methyl Ethyl MEthyl Methyl l90l92 Bromide l3 Methyl Methyl Methyl Ethyl Methyl Ethyl l44l45 Bromide l4 Methyl Methyl Methyl Ethyl ,B-CH -,O-ethyl ['1-CH;,O-ethyl 9 l-93 Oxalate l5 Methyl Methyl Methyl Ethyl Propyl Propyl 143- 1 45 Bromide 7 8 Continued Example R R R3 4 5 R6 5&1} form 1 6 Methyl Methyl Methyl Ethyl lsopropyl lsopropyl 1 32-1 34 Bromide 1 7 Methyl Methyl Methyl Ethyl Butyl Butyl l 2 l- 1 22 Bromide 1 8 Methyl Methyl Methyl Ethyl lsobutyl lsobutyl 1 60-1 62 Bromide 19 Methyl Methyl Methyl Ethyl Allyl Allyl 1 19-121 Bromide 20 Methyl Methyl Methyl Propyl Methyl Methyl 125- 1 27 Bromide 2 1 Methyl Methyl Methyl Propyl Ethyl Ethyl 1 -1 27 Bromide 22 Methyl Methyl Methyl Propyl fi CH o-ethyl fl-CH Oethyl 54-56 Bromide 2 3 Methyl Methyl Methyl Propyl Propyl Propyl 10 1-102" Bromide 24 Methyl Methyl Methyl Propyl lsopropyl lsopropyl 1 37-1 38 Bromide 25 Methyl Methyl Methyl Propyl lsobutyl lsobutyl 169-170 Bromide 26 Methyl Methyl Methyl Propyl Allyl Allyl 102-104 Oxalate 27 Methyl Methyl Methyl lsopropyl Ethyl Ethyl 1 5 1-152 Bromide 28 Methyl Methyl Methyl lsopropyl Propyl Propyl 1 1 9-1 20 Bromide 29 Methyl Methyl Methyl lsopropyl lsopropyl lsopropyl 17 l -172 Bromide 30 Methyl Methyl Methyl lsopropyl Allyl Allyl 126-128 Oxalate 31 Methyl Methyl Methyl Allyl Methyl Methyl ll42 Bromide 32 Methyl Methyl Methyl Allyl Ethyl Ethyl 136-1 37 Bromide 33 Methyl Methyl Methyl Allyl Propyl Propyl l40-l41 Bromide 34 Methyl Methyl Methyl Allyl lsopropyl lsopropyl 140-142 Bromide 3 5 Methyl Methyl Methyl Allyl lsobutyl lsobutyl 148-1 49 Bromide 36 Methyl Methyl Methyl Allyl Allyl Allyl 9394 Oxalate 37 Methyl Methyl Methyl Butyl Methyl Methyl 1 13-1 14 Bromide 38 Methyl Methyl Methyl Butyl Ethyl Ethyl 1 17-1 18'' Bromide 39 Methyl Methyl Methyl Butyl Propyl Propyl 79-80 Bromide 40 Methyl Methyl Methyl Butyl lsopropyl lsopropyl 1 30-1 32 Bromide 4 1 Methyl Methyl Methyl Butyl Butyl Butyl 78-82 Bromide 42 Methyl Methyl Methyl Butyl Allyl Allyl 30-8 1 Bromide 43 Methyl Methyl Methyl lsobutyl Ethyl Ethyl 192-1 94 Bromide 44 Methyl Methyl Methyl lsobutyl Propyl Propyl 103-104 Bromide 45 Methyl Methyl Methyl lsobutyl Allyl Allyl 96-98 Bromide 46 Methyl Methyl Methyl sec-Butyl Ethyl Ethyl 1 28-1 3 1 Bromide 47 Methyl Methyl Methyl sec-Butyl CH O-ethyl CH o-ethyl 83-84 Oxalate 48 Methyl Methyl Methyl sec-Butyl Propyl Propyl 1 13-1 14 Oxalate 49 Methyl Methyl Methyl sec-Butyl Allyl Allyl l04-105 Oxalate 50 Methyl Methyl Methyl tert-Butyl Ethyl Ethyl 1 38-1 39 Bromide 5 1 Methyl Methyl Methyl tert-Butyl lsopropyl lsopropyl 1 34-1 35 Bromide 5 2 Methyl Methyl Methyl Amyl Methyl Methyl 1 28-1 30 Bromide 53 Methyl Methyl Methyl Amyl Ethyl Ethyl 74-76 Oxalate 54 Methyl Methyl Methyl Amyl Propyl Propyl 60-6 1 Bromide 55 Methyl Methyl Methyl Amyl Allyl Allyl 82-B4 Oxalate 56 Methyl Methyl Methyl lsoamyl Ethyl Ethyl l 1 9-1 20 Bromide 57 Methyl Methyl Methyl Octyl Ethyl Ethyl 84-85 Bromide 58 Methyl Methyl Ethyl Ethyl Ethyl Ethyl 107-l09 Bromide 59 Methyl Methyl Ethyl Methyl lsobutyl lsobutyl 143-145 Bromide 60 Methyl Methyl Ethyl Ethyl Propyl Propyl 1 25-1 26 Oxalate 6 1 Methyl Methyl Ethyl Ethyl Allyl Allyl 87-88 Oxalate 62 Methyl Methyl Ethyl sec-Butyl Ethyl Ethyl 100l02 Bromide 63 Methyl Methyl Methyl Meth l Meth l Phenyl 189l92 Bromide 64 Methyl Methyl Methyl Ethy Ethy Phenyl 2 1 3-21 6 Bromide 65 Methyl Methyl Methyl I Phenyl Methyl Methyl 179182 Bromide 66 Methyl Methyl Methyl Phenyl Ethyl Ethyl 169-1 72 Bromide 67 Methyl Methyl Methyl Phenyl Propyl Propyl 18 1-182 Bromide 68 Methyl Methyl Methyl Phenyl Allyl Allyl 1 13-1 l5 Bromide 69 Methyl Methyl Methyl p-Cl-phenyl Ethyl Ethyl l 8 1-1 83 Bromide 70 Methyl Methyl Methyl p-C H -phenyl Ethyl Ethyl 162-163 Bromide 7 1 Methyl Methyl Phenyl Ethyl Ethyl Ethyl 143-1 44 Bromide 72 Methyl Methyl Ethyl Butyl Ethyl Ethyl 1 13-1 14 Bromide 73 Methyl Methyl Ethyl sec-Butyl Allyl Allyl 92-93 Oxalate 74 Methyl Methyl Methyl sec-Butyl lsopropyl lsopropyl 1 63-1 64 Bromide 75 Methyl Methyl Methyl Octyl Methy Methyl 127-1 28 Bromide 76 Methyl Methyl Methyl B-Methallyl Methyl Methyl 135-1 37 Bromide 77 Methyl Methyl Methyl B-Methallyl Ethyl Ethyl 153-1 55 Bromide 7 8 Methyl Methyl Methyl B-Methallyl Propyl Propyl 142- 1 43 Bromide 79 Methyl Methyl Methyl Hexyl Ethyl Ethyl 90-9 1 Oxalate 80 Methyl Methyl Methyl Butyl Methyl Ethyl 108-1 09 Bromide 8 1 Methyl Methyl Methyl Hexyl Methyl Methyl 1 28- 1 29 Bromide 82 Methyl Methyl Methyl lsobutyl Methyl Methyl 1 -1 86 Bromide 83 Methyl Methyl Methyl sec-Butyl Methyl Ethyl 98l00 Bromide 84 Methyl Methyl Methyl tert-Butyl Methyl Ethyl 1 63-1 64 Bromide 85 Methyl Methyl Methyl sec-Hexyl Methyl Methyl 8 l-82 Oxalate 86 Methyl Methyl Methyl Methyl lsoamyl lsoamyl l 64165 Bromide 87 Methyl Methyl Methyl lsoamyl Allyl Allyl 7475 Oxalate 88 Methyl Methyl Methyl sec-Hexyl Methyl Ethyl 108-1 10 Oxalate 89 Methyl Methyl Methyl Ethyl Z-Cyanoethyl 2-cyanoethy1 167- 1 68 Bromide 90 Methyl Methyl Methyl sec-Butyl Methyl 2-eyanoethyl 96 Oxalate 90A p-CH -phenyl Methyl Methyl fi-CH O-ethyl Ethyl Ethyl 90B p-cl-l -phenyl Methyl Methyl l=piperazine Alkyl Ethyl 90 C p-CH -,-phenyl Methyl Methyl Methyl p-CH -phenyl Ethyl v 90 D p-cH -phenyl Methyl Methyl Methyl p-Cl-phenyl Ethyl 90 E pentamethylene Methyl sec-Butyl Methyl Methyl 90 F tetramethylene Methyl sec-Butyl Methyl Methyl 9 1 Methyl Methyl Methyl Dimethylamino Ethyl Ethyl 19 3-195 Bromide 92 Methyl Methyl Methyl Methyl sec-Butyl sec-Butyl 107- 1 08 Oxalate 93 Methyl Butyl Methyl Methyl sec-Butyl sec-Butyl 85-86 Oxalate 94 Methyl Butyl Methyl Methyl lsobutyl lsobutyl 1 3 l-132 Oxalate 95 Methyl Butyl Methyl Ethyl Ethyl Ethyl 9 1 93 Bromide 96 Methyl Butyl Meth 1 ten-Butyl Ethyl Ethyl 113-1 14 Oxalate 97 Ethyl Ethyl Ethy Ethyl Ethyl Ethyl 1 55-1 56 Oxalate 98 Ethyl Ethyl Ethyl sec-Butyl Ethyl Ethyl 1 68-1 70 Oxalate 99 Ethyl Ethyl Ethyl Methyl sec-Butyl sec-Butyl 15 l- 1 52 Oxalate 1 ()0 Methyl Butyl Methyl sec-Butyl Ethyl Ethyl 1 20 Oxalate lOl Ethyl Ethyl Ethyl Methyl lsobutyl lsobutyl l 3 8-139 Bromide 102 Adamantyl Methyl lsobutyl lsobutyl 187-189 Bromide 103 Adamantyl Ethyl Ethyl Ethyl 240-242 Bromide Using the process exemplified in Example 1 or 2 and the appropriate starting materials, there are obtained the following compounds a) N.[CH 1 .CN

2 3 A cco.cu c

i 2 Et CH3 /N-N o co.cn c

Bt N C N-N en ccocu -c on I 3 %NN cir -cco.cu c l e) 011 I cn pCO.Ch -C What is claimed is: 1. A compound of the formula:

wherein R is alkyl of l to 4 carbon atoms, phenyl, substituted with halo or alkyl of l to 4 carbon atoms, and R is alkyl of l to 4 carbon atoms, or R and R together are (CH wherein n is an integer from 2 to 7, and

R is alkyl of 1 to 4 carbon atoms, R is alkyl of l to 8 carbon atoms, alkenyl of 2 to 8 carbon atoms, and R and R are the same or different and each is alkyl of l to 8 carbon atoms, alkenyl of 2 to 8 carbon atoms, or one of R R and R is phenyl or phenyl substituted with halo or alkyl of l to 4 carbon atoms and the others of R R and R are as defined above, or a salt thereof of a pharmaceutically acceptable acid.

2. A compound of the formula:

1x2 /N-R wherein R is alkyl of 1 to 4 carbon atoms, phenyl or phenyl mono-substituted with chloro or alkyl of l to 4 carbon atoms, and R is alkyl of l to 4 carbon atoms, or R and R together are (CH wherein n is an integer from 2 to 7, and

R is alkyl of l to 4 carbon atoms, R, is alkyl of l to 8 carbon atoms, or alkenyl of 2 to 8 carbon atoms and R and R are the same or different and each is alkyl of l to 8 carbon atoms or alkenyl of 2 to 8 carbon atoms or one of R R and R is phenyl or phenyl monosubstituted with chloro or alkyl of l to 4 carbon atoms and the others of R R and R are as defined above, or a salt thereof of a pharmaceutically acceptable acid.

3. A compound of claim 2, wherein R R and R are,

independently alkyl and R R and R are, independently, alkenyl or alkyl.

4. The compound of claim 3, which is N,N -triethyl- 4,4-dimethyl-3-oxo-pentanamidine.

5. The compound of claim 3, which is N ,N -diisobutyl-N,4,4-trimethyl-3-oxo-pentanamidine.

6. A compound of claim 2, wherein R R and R are methyl.

7. The compound of claim 6, wherein R, is methyl, R is methyl and R is methyl.

8. The compound of claim 6, wherein R, is methyl, R is methyl and R is ethyl.

9. The compound of claim 6, wherein R, is methyl, R is ethyl and R is ethyl.

10. The compound of claim 6, wherein R, is methyl, R is propyl and R is propyl.

11. The compound of claim 6, wherein R, is methyl, R is isopropyl and R is isopropyl.

12. The compound of claim 6, wherein R, is methyl, R is ally] and R is allyl.

13. The compound of claim 6, wherein R, is methyl, R is butyl and R is butyl.

14. The compound of claim 6, wherein R, is methyl, R is isobutyl and R is isobutyl.

15. The compound of claim 6, wherein R, is ethyl, R is methyl and R methyl.

16. The compound of claim 6, wherein R, is ethyl, R is methyl and R is ethyl.

17. The compound of claim 6, wherein R, is ethyl, R is propyl and R is propyl.

18. The compound of claim 6, wherein R, is ethyl, R is isopropyl and R is isopropyl.

19. The compound of claim 6, wherein R, is ethyl, R, is butyl and R is butyl.

20. The compound of claim 6, wherein R, is ethyl, R is isobutyl and R is isobutyl.

21. The compound of claim 6, wherein R, is ethyl, R is allyl and R is allyl.

22. The compound of claim 6, wherein R, is propyl, R is methyl and R is methyl.

23. The compound of claim 6, wherein R, is propyl, R is ethyl and R is ethyl.

24. The compound of claim 6, wherein R, is propyl, R is propyl and R is propyl.

25. The compound of claim 6, wherein R, is propyl, R is isopropyl and R6 is isopropyl.

26. The compound of claim 6, wherein R, is propyl, R isobutyl and R is isobutyl.

27. The compound of claim 6, wherein R, is propyl, R is allyl and R is allyl.

28. The compound of claim 6, wherein R, is isopropyl, R is ethyl and R is ethyl.

29. The compound of claim 6, wherein R, is isopropyl, R is propyl and R is propyl.

30. The compound of claim 6, wherein R, is isopropyl, R is isopropyl and R is isopropyl.

31. The compound of claim 6, wherein R, is isopropyl, R is allyl and R is allyl.

32. The compound of claim 6, wherein R, is allyl, R is methyl and R is methyl.

33. The compound of claim 6, wherein R, is allyl, R is ethyl and R is ethyl.

34. The compound of claim 6, wherein R, is allyl, R is propyl and R is propyl.

35. The compound of claim 6, wherein R, is allyl, R is isopropyl and R is isopropyl.

36. The compound of claim 6, wherein R, is allyl, R is isobutyl and R is isobutyl.

37. The compound of claim 6, wherein R, is allyl, R is allyl and R is allyl.

38. The compound of claim 6, wherein R, is butyl, R is methyl and R is methyl.

39. The compound of claim 6, wherein R, is butyl, R is ethyl and R is ethyl.

44. The compound of claim 6, wherein R, is isobutyl,

R is ethyl and R, is ethyl.

45. The compound of claim 6, wherein R, is isobutyl, R is propyl and R is propyl.

46. The compound of claim 6, wherein R, is isobutyl, R is allyl and R is allyl.

47. The compound of claim 6, wherein R, is seebutyl, R is ethyl and R is ethyl.

48. The compound of claim 6, wherein R, is secbutyl, R is propyl and R is propyl.

49. The compound of claim 6, wherein R, is seebutyl, R is allyl and R is allyl.

50. The compound of claim 6, wherein R, is tertbutyl, R is ethyl and R is ethyl.

51. The compound of claim 6, wherein R, is tertbutyl, R is isopropyl and R is isopropyl.

52. The compound of claim 6, wherein R, is amyl, R is methyl and R is methyl.

53. The compound of claim 6, wherein R, is amyl, R is ethyl and R is ethyl.

54. The compound of claim 6, wherein R, is amyl, R is propyl and R, is propyl.

55. The compound of claim 6, wherein R, is amyl, R is allyl and R allyl.

56. The compound of claim 6, wherein R, is isoamyl, R is ethyl and R is ethyl.

57. The compound of claim 6, wherein R, is octyl, R is ethyl and R is ethyl.

58. The compound of claim 6, wherein R, is methyl, R is methyl and R phenyl.

59. The compound of claim 6, wherein R, is ethyl, R is ethyl and R is phenyl.

60. The compound of claim 6, wherein R, is phenyl, R is methyl and R is methyl.

61. The compound of claim 6, wherein R, is phenyl, R is ethyl and R, is ethyl.

62. The compound of claim 6, wherein R, is phenyl, R is propyl and R, is propyl.

63. The compound of claim 6, wherein R, is phenyl, R is allyl and R is allyl.

64. The compound of claim 6, wherein R, is p-Clphenyl, R is ethyl and R, is ethyl.

65. The compound of claim 6, wherein R, is p-CH;,- phenyl, R is ethyl and R is ethyl.

66. The compound of claim 6, wherein R, is secbutyl, R is isopropyl and R is isopropyl.

67. The compound of claim 6, wherein R, is octyl, R is methyl and R is methyl.

68. The compound of claim 6, wherein R, is ,B-methallyl, R is methyl and R is methyl.

69. The compound of claim 6, wherein R, is B-methallyl, R is ethyl and R, is ethyl.

70. The compound of claim 6, wherein R is B-meth allyl, R, is propyl and R is propyl.

71. The compound of claim 6, wherein R, is hexyl, R is ethyl and R,, is ethyl.

72. The compound of claim 6, wherein R, is butyl, R is methyl and R is ethyl.

73. The compound of claim 6, wherein R,, is hexyl, R is methyl and R,, is methyl.

74. The compound of claim 6, wherein R is isobutyl, R is methyl and R,, is methyl.

75. The compound of claim 6, wherein R is secbutyl, R,, is methyl and R,, is ethyl.

76. The compound of claim 6, wherein R,, is tertbutyl, R is methyl and R,, is ethyl.

77. The compound of claim 6, wherein R,, is sechexyl, R is methyl and R is methyl.

78. The compound of claim 6, wherein R,, is methyl, R is isoamyl and R,, is isoamyl.

79. The compound of claim 6, wherein R, is isoamyl, R,, is allyl and R,, is allyl.

80. The compound of claim 6, wherein R, is sechexyl, R is methyl and R,, is ethyl.

81. A compound of claim 2, wherein R, and R are methyl and R is ethyl.

82. The compound of claim 81, wherein R, is ethyl, R,, is ethyl and R,, is ethyl.

83. The compound of claim 81, wherein R,, is methyl, R is isobutyl and R,, is isobutyl.

84. The compound of claim 81, wherein R is ethyl, R is propyl and R,, is propyl.

85. The compound of claim 81, wherein R, is ethyl, R is allyl and R,, is allyl.

86. The compound of claim 81, wherein R, is secbutyl, R is ethyl and R ethyl.

87. The compound of claim 81, wherein R is butyl, R is ethyl and R is ethyl.

88. The compound of claim 81, wherein R is secethyl.

93. The compound of claim 2, wherein R, to R,, are ethyl.

94. The compound of claim 2, wherein R,, R R R and R,, are ethyl and R,, is sec-butyl.

95. The compound of claim 2, wherein R, to R,, are ethyl, R, is methyl and R and R,, are sec-butyl.

96. The compound of claim 2, wherein R, and R are methyl, R is butyl, R, is sec-butyl and R and R,, are ethyl.

97. The compound of claim 2, wherein R, to R are ethyl, R, is methyl and R and R,,- are isobutyl. 

1. A COMPOUND OF THE FORMULA:
 2. A compound of the formula:
 3. A compound of claim 2, wherein R1, R2 and R3 are, independently alkyl and R4, R5 and R6 are, independently, alkenyl or alkyl.
 4. The compound of claim 3, which is N1,N2-triethyl-4,4-dimethyl-3-oxo-pentanamidine.
 5. The compound of claim 3, which is N2,N2-di-isobutyl-N1,4,4-trimethyl-3-oxo-pentanamidine.
 6. A compound of claim 2, wherein R1, R2 and R3 are methyl.
 7. The compound of claim 6, wherein R4 is methyl, R5 is methyl and R6 is methyl.
 8. The compound of claim 6, wherein R4 is methyl, R5 is methyl and R6 is ethyl.
 9. The compound of claim 6, wherein R4 is methyl, R5 is ethyl and R6 is ethyl.
 10. The compound of claim 6, wherein R4 is methyl, R5 is propyl and R6 is propyl.
 11. The compound of claim 6, wherein R4 is methyl, R5 is isopropyl and R6 is isopropyl.
 12. The compound of claim 6, wherein R4 is methyl, R5 is allyl and R6 is allyl.
 13. The compound of claim 6, wherein R4 is methyl, R5 is butyl and R6 is butyl.
 14. The compound of claim 6, wherein R4 is methyl, R5 is isobutyl and R6 is isobutyl.
 15. The compound of claim 6, wherein R4 is ethyl, R5 is methyl and R6 methyl.
 16. The compound of claim 6, wherein R4 is ethyl, R5 is methyl and R6 is ethyl.
 17. The compound of claim 6, wherein R4 is ethyl, R5 is propyl and R6 is propyl.
 18. The compound of claim 6, wherein R4 is ethyl, R5 is isopropyl and R6 is isopropyl.
 19. The compound of claim 6, wherein R4 is ethyl, R5 is butyl and R6 is butyl.
 20. The compound of claim 6, wherein R4 is ethyl, R5 is isobutyl and R6 is isobutyl.
 21. The compound of claim 6, wherein R4 is ethyl, R5 is allyl and R6 is allyl.
 22. The compound of claim 6, wherein R4 is propyl, R5 is methyl and R6 is methyl.
 23. The compound of claim 6, wherein R4 is propyl, R5 is ethyl and R6 is ethyl.
 24. The compound of claim 6, wherein R4 is propyl, R5 is propyl and R6 is propyl.
 25. The compound of claim 6, wherein R4 is propyl, R5 is isopropyl and R6 is isopropyl.
 26. The compound of claim 6, wherein R4 is propyl, R5 isobutyl and R6 is isobutyl.
 27. The compound of claim 6, wherein R4 is propyl, R5 is allyl and R6 is allyl.
 28. The compound of claim 6, wherein R4 is isopropyl, R5 is ethyl and R6 is ethyl.
 29. The compound of claim 6, wherein R4 is isopropyl, R5 is propyl and R6 is propyl.
 30. The compound of claim 6, wherein R4 is isopropyl, R5 is isopropyl and R6 is isopropyl.
 31. The compound of claim 6, wherein R4 is isopropyl, R5 is allyl and R6 is allyl.
 32. The compound of claim 6, wherein R4 is allyl, R5 is methyl and R6 is methyl.
 33. The compound of claim 6, wherein R4 is allyl, R5 is ethyl and R6 is ethyl.
 34. The compound of claim 6, wherein R4 is allyl, R5 is propyl and R6 is propyl.
 35. The compound of claim 6, wherein R4 is allyl, R5 is isopropyl and R6 is isopropyl.
 36. The compound of claim 6, wherein R4 is allyl, R5 is isobutyl and R6 is isobutyl.
 37. The compound of claim 6, wherein R4 is allyl, R5 is allyl and R6 is allyl.
 38. The compound of claim 6, wherein R4 is butyl, R5 is methyl and R6 is methyl.
 39. The compound of claim 6, wherein R4 is butyl, R5 is ethyl and R6 is ethyl.
 40. The compound of claim 6, wherein R4 is butyl, R5 is propyl and R6 is propyl.
 41. The compound of claim 6, wherein R4 is butyl, R5 is isopropyl and R6 is isopropyl.
 42. The compound of claim 6, wherein R4 is butyl, R5 is butyl and R6 is butyl.
 43. The compound of claim 6, wherein R4 is butyl, R5 is allyl and R6 is allyl.
 44. The compound of claim 6, wherein R4 is isobutyl, R5 is ethyl and R6 is ethyl.
 45. The compound of claim 6, wherein R4 is isobutyl, R5 is propyl and R6 is propyl.
 46. The compound of claim 6, wherein R4 is isobutyl, R5 is allyl and R6 is allyl.
 47. The compound of claim 6, wherein R4 is sec-butyl, R5 is ethyl and R6 is ethyl.
 48. The compound of claim 6, wherein R4 is sec-butyl, R5 is propyl and R6 is propyl.
 49. The compound of claim 6, wherein R4 is sec-butyl, R5 is allyl and R6 is allyl.
 50. The compound of claim 6, wherein R4 is tert-butyl, R5 is ethyl and R6 is ethyl.
 51. The compound of claim 6, wherein R4 is tert-butyl, R5 is isopropyl and R6 is isopropyl.
 52. The compound of claim 6, wherein R4 is amyl, R5 is methyl and R6 is methyl.
 53. The compound of claim 6, wherein R4 is amyl, R5 is ethyl and R6 is ethyl.
 54. The compound of claim 6, wherein R4 is amyl, R5 is propyl and R6 is propyl.
 55. The compound of claim 6, wherein R4 is amyl, R5 is allyl and R6 allyl.
 56. The compound of claim 6, wherein R4 is isoamyl, R5 is ethyl and R6 is ethyl.
 57. The compound of claim 6, wherein R4 is octyl, R5 is ethyl and R6 is ethyl.
 58. The compound of claim 6, wherein R4 is methyl, R5 is methyl and R6 phenyl.
 59. The compound of claim 6, wherein R4 is ethyl, R5 is ethyl and R6 is phenyl.
 60. The compound of claim 6, wherein R4 is phenyl, R5 is methyl and R6 is methyl.
 61. The compound of claim 6, wherein R4 is phenyl, R5 is ethyl and R6 is ethyl.
 62. The compound of claim 6, wherein R4 is phenyl, R5 is propyl and R6 is propyl.
 63. The compound of claim 6, wherein R4 is phenyl, R5 is allyl and R6 is allyl.
 64. The compound of claim 6, wherein R4 is p-Cl-phenyl, R5 is ethyl and R6 is ethyl.
 65. The compound of claim 6, wherein R4 is p-CH3-phenyl, R5 is ethyl and R6 is ethyl.
 66. The compound of claim 6, wherein R4 is sec-butyl, R5 is isopropyl and R6 is isopropyl.
 67. The compound of claim 6, wherein R4 is octyl, R5 is methyl and R6 is methyl.
 68. The compound of claim 6, wherein R4 is Beta -methallyl, R5 is methyl and R6 is methyl.
 69. The compound of claim 6, wherein R4 is Beta -methallyl, R5 is ethyl and R6 is ethyl.
 70. The compound of claim 6, wherein R5 is Beta -methallyl, R5 is propyl and R6 is propyl.
 71. The compound of claim 6, wherein R4 is hexyl, R5 is ethyl and R6 is ethyl.
 72. The compound of claim 6, wherein R4 is butyl, R5 is methyl and R6 is ethyl.
 73. The compound of claim 6, wherein R4 is hexyl, R5 is methyl and R6 is methyl.
 74. The compound of claim 6, wherein R4 is isobutyl, R5 is methyl and R6 is methyl.
 75. The compound of claim 6, wherein R4 is sec-butyl, R5 is methyl and R6 is ethyl.
 76. The compound of claim 6, wherein R4 is tert-butyl, R5 is methyl and R6 is ethyl.
 77. The compound of claim 6, wherein R4 is sec-hexyl, R5 is methyl and R6 is methyl.
 78. The compound of claim 6, wherein R4 is methyl, R5 is isoamyl and R6 is isoamyl.
 79. The compound of claim 6, wherein R4 is isoamyl, R5 is allyl and R6 is allyl.
 80. The compound of claim 6, wherein R4 is sec-hexyl, R5 is methyl and R6 is ethyl.
 81. A compound of claim 2, wherein R1 and R2 are methyl and R3 is ethyl.
 82. The compound of claim 81, wherein R4 is ethyl, R5 is ethyl and R6 is ethyl.
 83. The compound of claim 81, wherein R4 is methyl, R5 is isobutyl and R6 is isobutyl.
 84. The compound of claim 81, wherein R4 is ethyl, R5 is propyl and R6 is propyl.
 85. The compound of claim 81, wherein R4 is ethyl, R5 is allyl and R6 is allyl.
 86. The compound of claim 81, wherein R4 is sec-butyl, R5 is ethyl and R6 ethyl.
 87. The compound of claim 81, wherein R4 is butyl, R5 is ethyl and R6 is ethyl.
 88. The compound of claim 81, wherein R4 is sec-butyl, R5 is allyl and R6 is allyl.
 89. The compound of claim 2, wherein R1, R3 and R4 are methyl, R2 is butyl and R5 and R6 are sec-butyl.
 90. The compound of claim 2, wherein R1, R3 and R4 are methyl, R2 is butyl and R5 and R6 are isobutyl.
 91. The compound of claim 2, wherein R1 and R3 are methyl, R2 is butyl and R4, R5 and R6 are ethyl.
 92. The compound of claim 2, wherein R1 and R3 are methyl, R2 is butyl, R4 is tert-butyl and R5 and R6 are ethyl.
 93. The compound of claim 2, wherein R1 to R6 are ethyl.
 94. The compound of claim 2, wherein R1, R2, R3, R5 and R6 are ethyl and R4 is sec-butyl.
 95. The compound of claim 2, wherein R1 to R3 are ethyl, R4 is methyl and R5 and R6 are sec-butyl.
 96. The compound of claim 2, wherein R1 and R3 are methyl, R2 is butyl, R4 is sec-butyl and R5 and R6 are ethyl.
 97. The compound of claim 2, wherein R1 to R3 are ethyl, R4 is methyl and R5 and R6 are isobutyl. 